Pharmacol Res Perspect. 2019;00:e00501. | 1 of 10
https://doi.org/10.1002/prp2.501
wileyonlinelibrary.com/journal/prp2 Received: 6 March 2019
|
Revised: 14 June 2019|
Accepted: 16 June 2019DOI: 10.1002/prp2.501
O R I G I N A L A R T I C L E
Prenatal exposure to opioid maintenance treatment and neonatal outcomes: Nationwide registry studies from the Czech Republic and Norway
Marte Handal
1| Blanka Nechanská
2,3| Svetlana Skurtveit
1,4| Ingunn Olea Lund
1| Roman Gabrhelík
2| Anders Engeland
5,6| Viktor Mravčík
2,7This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
© 2019 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.
Abbreviations: ATC, Anatomical Therapeutic Chemical; NAS, neonatal abstinence syndrome; OMT, Opioid maintenance treatment; ORs, odds ratios; SGA, small for gestational age.
1Department of Mental
Disorders, Norwegian Institute of Public Health, Oslo, Norway
2Department of Addictology, First Faculty of Medicine, Charles University, Prague, Czech Republic
3Institute of Health Information and Statistics of the Czech Republic, Prague, Czech Republic
4Norwegian Centre for Addiction Research at the University of Oslo, Oslo, Norway
5Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway
6Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
7National Monitoring Centre for Drugs and Addiction, Office of the Government of the Czech Republic, Prague, Czech Republic Correspondence
Marte Handal, Norwegian Institute of Public Health, Department of Mental Disorders, PO Box 222 Skøyen, N‐0213 Oslo, Norway.
Email: [email protected] Funding information
Norges Forskningsråd, Grant/Award Number: 240197/H10.; Ministerstvo Zdravotnictví Ceské Republiky, Grant/Award Number: PRVOUK‐P03/LF1/9; Ministry of Health, Grant/Award Number: 16‐28157A, LF1 and 9; Norwegian Research Council, Grant/Award Number: 240197 and H10
Abstract
There is lack of knowledge about the safety of treatment with methadone and bu‐
prenorphine as part of opioid maintenance treatment (OMT) during pregnancy. The purpose of this study was to examine neonatal outcomes concerning the use of OMT during pregnancy. We used nationwide registry linkages from the Czech Republic (2000‐2014) and Norway (2004‐2013). We compared prenatally OMT–exposed newborns with (a) newborns of women hospitalized with opioid use disorder during pregnancy in the Czech sample and (b) newborns with neonatal abstinence syndrome (NAS) in Norway. We performed multivariate linear and binary logistic regression exploring the associations between OMT and neonatal outcomes (growth param‐
eters, gestational age, fetal death, small for gestational age, Apgar score, and NAS).
Regression coefficients (b) and odds ratios (ORs) were estimated. The cohorts con‐
sisted of 333 Czech, and 235 Norwegian OMT–exposed newborns, and 106 and 294 newborns in the comparison groups, respectively. In both countries, the neonatal growth parameters were similar in the OMT and the comparison groups. In Norway, OMT exposure prolonged gestational age (adjusted b = 0.96 weeks, 95% confi‐
dence interval [CI] =0.39‐1.53) while the odds of preterm birth and Apgar score at 5 minutes were lower than in the comparison group (adjusted OR = 0.35, 0.16‐0.75 and aOR = 0.21, 0.06‐0.78, respectively). Newborns of women in OMT had similar growth parameters as newborns of women with opioid use disorders who were not in OMT during pregnancy. Overall, our findings do not suggest that OMT results in worse neonatal outcomes.
K E Y W O R D S
buprenorphine, methadone, neonate, opioid maintenance treatment, prenatal exposure
1 | INTRODUCTION AND BACKGROUND
Opioid use disorder is characterized by the persistent use of opi‐
oids despite the adverse consequences of its use. Opioid mainte‐
nance treatment (OMT) can stabilize women and reduce the risk of relapse to illicit opioid use.1 The World Health Organization (WHO) strongly recommends women with opioid use disorders to con‐
tinue or commence OMT with either methadone or buprenorphine if they become pregnant, despite the meager evidence behind this recommendation.2
Previous research has emphasized benefits with OMT during pregnancy. If left untreated, opioid use disorders during pregnancy are associated with a range of obstetric and neonatal complications, such as spontaneous abortions, intrauterine growth retardation, preterm birth, and low Apgar score.3 Since methadone mainte‐
nance treatment was introduced in the US in the late 1960s, stud‐
ies have reported beneficial effects, such as reduced incidence of obstetric and fetal complications, neonatal morbidity and mortality, from methadone therapy compared to illicit heroin use during preg‐
nancy.4‐6 Maintenance treatment with buprenorphine has later been shown to be comparable to that of methadone.7,8
OMT is, however, also associated with disadvantages. Neonates exposed to opioid agonist therapy have higher rates of adverse neo‐
natal outcomes compared to neonates in the general population.
There is evidence of high rates of neonatal abstinence syndrome (NAS), lower birth weight, length, and head circumference as well as increased rates of perinatal mortality.9‐11 The incidence and se‐
verity of NAS are not only higher after opioid agonist therapy when compared to the general population; it seems to be higher after exposure to methadone than after exposure to heroin.6
With an increasing focus on preventing harm to the unborn child, the low evidence behind OMT has resulted in critical questions from pregnant woman, clinicians, researchers,12,13 policymakers, and pol‐
iticians about the safety of OMT during pregnancy.
Previous studies have several weaknesses, including one major concern of unmeasured confounding. Most studies only compare newborns of women in OMT during pregnancy with newborns of women from the general population. Women in these two groups have very different confounder distributions, and comparison be‐
tween them is therefore not suitable. Using appropriate comparison groups is one way to come closer to an unbiased association. Many of the studies were also conducted several years ago, and often in selected populations. Many were performed in countries where the quality of health care differs for different patient populations, mak‐
ing a comparison between groups difficult.7,14‐18
Moreover, OMT has changed substantially since methadone was first introduced and since the early studies were conducted:
more pharmacological options have been introduced, and inclu‐
sion and exclusion criteria for OMT have changed. In light of these changes, exploring these questions in new settings and using new approaches may contribute to shed more light on the problem.
Use of data from nationwide health registries is a new approach
that makes it possible to address several of the limitations from earlier studies.19 Linking data from multiple registries allows for large, unselected study populations and identification of relevant comparison groups.
To increase the knowledge about the safety of OMT treatment during pregnancy, we utilize nationwide registry data from two dif‐
ferent European countries to study associations between OMT ex‐
posure and adverse neonatal outcomes in newborns. To reduce the problem of unmeasured confounding, we compared newborns born to women who were in OMT during pregnancy to newborns whose mothers had indications of opioid use disorders but who were not in OMT during pregnancy.
2 | MATERIALS AND METHODS
2.1 | Study design
The study is an observational cohort study with two national co‐
horts based on linkages of nationwide registries.
2.2 | Setting
OMT became available for pregnant women in 1997 in the Czech Republic and in 1998 in Norway.20,21 In both countries, OMT is provided predominantly in an outpatient setting where metha‐
done, buprenorphine, and buprenorphine/naloxone are used as drugs. In the Czech Republic, methadone is dispensed in special‐
ized facilities free of charge, while buprenorphine–based drugs are available in community pharmacies and are typically fully paid by the patient. In Norway, most pregnant women in OMT receive their OMT drugs at pharmacies free of charge as part of a national OMT program.22
2.3 | Data sources
Both the Czech Republic and the Norway have nationwide registries with personal identification numbers. This enables linkages of data between different registries on an individual level, and on family lev‐
els such as between mother and child. A more detailed description of the data sources is provided elsewhere.8,22,23
2.4 | Registries in the Czech Republic
In the Czech Republic, physicians are obliged by law to report data to the national health registries.
2.4.1 | National Registry of Reproduction Health (NRRH)
The NRRH includes information about all women and their children during pregnancy, delivery, and puerperium. For instance, maternal var‐
iables such as demographic and socioeconomic data, alcohol, tobacco,
and illegal drug use during pregnancy and information about the deliv‐
ery are included in the registry. Information about the newborn, such as birth parameters, congenital malformations, and death, is also included.
2.4.2 | The National Registry of Addiction Treatment (NRAT)
The NRAT contains data on all patients starting and terminating dif‐
ferent addiction treatments. It includes, for instance, information about patients who receive OMT, such as date of treatment initiation and termination and type of OMT drug.
2.4.3 | The National Registry of Hospitalized Patients
The NRIT includes information on every episode of all types of hospitalizations, including information on dates of admission and discharge from the hospital. Diagnoses on the discharge summary are coded according to the International Statistical Classification of Diseases, 10th Revision (ICD‐10).
2.5 | Registries in Norway
2.5.1 | The Medical Birth Registry of Norway (MBRN)
The MBRN is based on a compulsory notification of every birth or late abortion from physicians or midwives attending the birth. The MBRN includes information concerning all births and late abortions from the 12th gestational week and onwards. The registry includes information concerning pregnancy, delivery, and the newborn.
Maternal data are also collected, such as demographic and socioeco‐
nomic backgrounds of the pregnant women and also tobacco smok‐
ing during pregnancy. Information about neonatal outcomes, such as gestational age, birth parameters, NAS, and congenital malforma‐
tions, are also included.
2.5.2 | The Norwegian Prescription Database (NorPD)
Pharmacies are obliged by law to forward prescription data to the NorPD. The NorPD includes information about all prescription drugs, including OMT drugs, dispensed at pharmacies to patients in ambula‐
tory care. For each prescription, the dispensing date and detailed in‐
formation on the drug is registered. The drugs are classified according to the Anatomical Therapeutic Chemical (ATC) classification system.24
2.5.3 | Statistics Norway (SSB)
From Statistics Norway we included information about maternal education. Educational institutions are obliged to report completed education on an individual level to SSB.
2.6 | Study population and study period
The study populations were pregnant women and their children born during the study period: 2000‐2014 in the Czech Republic (N = 1 547 273) and 2004‐2013 in Norway (N = 554 310). From this population, we identified women who had indications of opioid use disorders during pregnancy, who were either in OMT during preg‐
nancy or not in OMT.
2.7 | Exposure to OMT drugs during pregnancy
Exposure was defined as the use of the OMT drugs methadone or buprenorphine during pregnancy. In the Czech Republic, data on ini‐
tiation and termination of drug treatment from the NRRH were used to identify if women were receiving OMT drugs during pregnancy.
Of the 333 women who were in OMT treatment during pregnancy, 192 (58%) were in OMT throughout the entire pregnancy, while 141 (42%) were in OMT for only parts of pregnancy (mean 115 days of treatment, minimum 6 days and maximum 250 days).
In Norway, NorPD was used to identify women using OMT drugs. Those who were dispensed OMT drugs at least once during pregnancy were defined as exposed to OMT during pregnancy.
More than 95% of all OMT women receive more than one prescrip‐
tion of an OMT drug during pregnancy. Pregnant women in OMT receive, on average, a total amount of buprenorphine corresponding to approximately 10 mg/day in pregnancy, while women who use methadone on average receive a total amount of about 65 mg/day.
Approximately 80% of the OMT drugs are dispensed at pharmacies both early and late in the pregnancy. This suggests that they used these drugs throughout their pregnancy.
2.8 | Outcomes
The outcomes studied were neonatal outcomes identified in the NRRH or MBRN, and included: gestational age, preterm birth (<37 weeks of gestation), growth parameters (birth weight, length and head circumference), small for gestational age (SGA),25 miscar‐
riage (death of a fetus between gestational week 12 and 22), still‐
birth (death of a fetus in gestational week 22 or later), NAS (only in the Norwegian cohort), and Apgar scores < 7 at 1 and 5 minutes.
2.9 | Confounding variables
We obtained information on sociodemographic variables and life‐
style from the NRRH in the Czech Republic and from the MBRN and SSB in Norway. This information included age and marital status (registered as not married, married or unknown; in Norway, the mar‐
ried category also included living with a partner). Information about education was provided in the following categories: primary, sec‐
ondary, university, or unknown. Information about occupation was only available in the Czech Republic, and included the categories unemployed, employed and unknown. Information on recreational
drug use during pregnancy, that is, use of alcohol and illicit drugs was only available in the Czech Republic. Information about tobacco smoking was available in both countries and categorized as yes, no, or unknown.
2.10 | Comparison groups
To be able to study the safety of the OMT in pregnancy we created relevant but different comparison groups in the two countries by identifying pregnant women with indications of opioid use disorders who were not in OMT during pregnancy.
For the Czech comparison group, we selected pregnant women who, according to the NRIT, had been hospitalized during preg‐
nancy with a diagnosis at discharge indicating that she had an opioid use disorder (F11.X “mental or behavioral disorder due to opioid use” according to the International Statistical Classification of Diseases, 10th Revision [ICD‐10]). Furthermore, the women could not have received OMT during pregnancy, according to the NRAT.
The Norwegian control group comprised of women who, accord‐
ing to data in the MBRN, gave birth to a child with NAS. Newborns with NAS were recognized if they have received an ICD‐10 diagnosis of “neonatal withdrawal symptoms from maternal use of drugs of ad‐
diction” (P96.1 according to ICD‐10). When reporting to the registry, the midwife or physician could also tick a box for abstinence if neo‐
natal irritability and neurological symptoms had been observed and there was documentation of maternal abuse of prescription drugs, alcohol or illicit drugs during pregnancy, or the woman herself gave such information. Furthermore, the women in the comparison group could not have received OMT during pregnancy, according to the NorPD.
2.11 | Analysis strategy and statistics
In a previous study using the same nationwide registry data as in this study,8 we did not find any significant differences in risks of adverse neonatal outcomes between prenatal exposure to methadone or buprenorphine. Thus in this study, we collapsed the buprenorphine and methadone–treated women into one OMT–exposed group in each country. Then, in each country, we compared the OMT group with the comparison group in that country. First, we present soci‐
odemographic background and substance use during pregnancy.
Next, we focus on descriptive statistics (mean, standard deviation, percentages with 95% confidence intervals) on neonatal outcomes, restricted to singleton births in both countries. Growth param‐
eters (except SGA) were restricted to term births (≥37 gestational weeks). Gestational age, SGA, and Apgar scores were restricted to live births. Confidence Intervals for proportions were calculated using the continuity–corrected score interval method.26 Linear and logistic regression analyses were performed to investigate the as‐
sociation between OMT use in pregnancy (yes/no ‐ independent variable) and different neonatal outcomes (growth parameters,
gestational age, fetal death, small for gestational age, Apgar score, and NAS ‐ dependent variable). Associations were shown as regres‐
sion coefficients (b) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes both with 95% confidence intervals.
Unadjusted and adjusted b and ORs were estimated. The following factors were included in the adjusted multivariate regression analy‐
sis: age, marital status, education, and smoking. The statistical sig‐
nificance level was set to 0.05. Statistical analyses were conducted using SPSS v21 for Windows.
In supplementary tables, we show maternal socioeconomic char‐
acteristics, as well as neonatal outcomes in the OMT–exposed new‐
borns compared to newborns of women in OMT before and after (but not during) pregnancy and compared to all the children in the general population.
2.12 | Ethics
The study was approved by the Institutional Review Board of the General University Hospital in Prague (IRB00002705), the Regional Committees for Medical and Health Research Ethics (REK, AE:
2012‐222), and the Norwegian Data Inspectorate.
3 | RESULTS
3.1 | Background characteristics
In the Czech Republic, 333 women were in OMT during pregnancy, while 106 had opioid use disorder without being in OMT during pregnancy. In Norway, we identified 235 women who were in OMT during pregnancy, while 294 had indications of opioid use disor‐
der but were not in OMT during pregnancy. Tables 1 and 2 display maternal background characteristics. In both countries, women in the comparison groups were younger than women in OMT. In the Norwegian sample, the pregnant women in the OMT group had lower education levels (primary education 71.5% versus 50.0%) and higher smoking prevalence (68.5% versus 57.2%) during pregnancy than the comparison group (Table 2).
3.2 | Neonatal outcomes – descriptive statistics
Table 3 shows that most neonatal outcomes were similar in the OMT group and the comparison group in both countries. In the Czech Republic, the gestational age was similar between the OMT‐exposed and the comparison group (38.4 weeks), while in Norway the OMT‐
exposed had 0.9 weeks longer gestational age than those not ex‐
posed. Similarly the proportion with preterm birth was about the same in the OMT‐exposed and not exposed in the Czech Republic (16.9% and 14.4%), while in Norway the proportion in the OMT‐ex‐
posed was about half of that in the not exposed group (7.0% ver‐
sus 15.0%). Overall, the differences in neonatal outcomes between the OMT‐exposed and not exposed were negligible in the Czech Republic. Independent of exposure to OMT or not, the mean growth
parameters (birth weight, length, and head circumference) were lower in the Czech Republic than in Norway.
3.3 | Neonatal outcomes – regression analyses
Table 4 shows the results of linear and logistic regression analyses on birth outcomes comparing the OMT group to the comparison group in each country. The regression analysis of the OMT group versus the comparison group showed statistically significant ef‐
fects in Norway: gestational age (unadjusted b = 0.93 weeks), pre‐
term birth (unadjusted OR = 0.44), and low Apgar score at 5 minutes (unadjusted OR = 0.26). After adjustment for confounding factors the risk estimates of OMT exposure compared to no exposure were still significant; gestational age was nearly one week longer in OMT‐exposed (adjusted b = 0.96 weeks, 95% CI = 0.39‐1.53). OMT exposure also reduced the risk of preterm birth preterm birth (ad‐
justed OR = 0.35, CI = 0.16‐0.75) and the risk of low Apgar score at
5 minutes (adjusted OR = 0.21, CI = 0.06‐0.78). OMT was not signifi‐
cantly associated with a difference in any of the neonatal outcomes in the Czech cohort.
3.4 | Supplementary tables
Tables S1 and S2 show background characteristics and the neo‐
natal outcomes of the groups of women who were in OMT during pregnancy or who were in OMT before and after but not during pregnancy, and all pregnant women and their children (the general population of pregnant women) in both countries, respectively. The groups of women in both countries who at any time had received OMT differed from the pregnant women in the general population in that they had lower education, fewer were married or living with a partner, and more of them smoked (Table S1). Concerning neo‐
natal outcomes in the Czech Republic, gestational age and growth parameters were quite similar in newborns of women who at some Czech Republic
OMT (n = 333) No OMTa (n = 106)
n % 95% CI n % 95% CI
Age, y
≤24 98 29.4 24.7‐34.7 74 69.8 60.0‐78.2
25‐29 139 41.7 36.4‐47.3 21 19.8 13.0‐28.9
30‐34 77 23.1 18.8‐28.1 8 7.5 3.6‐14.8
≥35 19 5.7 3.6‐8.9 3 2.8 0.7‐8.7
Marital status
Not married 266 79.9 75.1‐84.0 87 82.1 73.2‐88.6
Married 49 14.7 11.2‐19.9 10 9.4 4.9‐17.1
Unknown 18 5.4 3.3‐8.6 9 8.5 4.2‐15.9
Education
Primary 159 47.7 42.3‐53.3 61 57.5 47.6‐67.0
Secondary 154 46.2 40.8‐51.8 42 39.6 30.4‐49.6
University 4 1.2 0.4‐3.3 0 0 0.0‐3.4
Unknown 16 4.8 2.9‐7.8 3 2.8 0.7‐8.7
Occupation
Unemployed 274 82.3 77.7‐86.1 96 90.6 82.3‐95.1
Employed 25 7.5 5.0‐11.0 10 9.4 4.9‐17.1
Unknown 34 10.2 7.3‐14.1 0 0 0.0‐3.4
Using of addictive substances during pregnancy
Alcohol 17 5.1 3.1‐8.2 6 5.7 2.3‐12.4
Smoking 136 40.8 35.6‐46.4 43 40.6 31.3‐50.6
Illicit drugs 129 38.7 33.5‐44.2 43 40.6 31.3‐50.6
Deliveries by multiplicity
Single 324 97.3 94.8‐98.7 106 100 96.6‐100.0
Twins and more 9 2.7 1.3‐5.3 0 0 0.0‐3.4
Abbreviation: CI, confidence interval
aWomen hospitalized with an ICD‐10 F11 diagnosis as a primary or secondary diagnosis during pregnancy were included.
TA B L E 1 Socioeconomic characteristics of Czech women with indications of opioid dependence who received opioid maintenance treatment (OMT) or not during pregnancy (2000‐2014)
time had been exposed to OMT irrespective of if this was during pregnancy or not (Table S2). In Norway, the number of pregnancies where the mother had used OMT before or after pregnancy, but not during pregnancy, was very less. In both countries, the growth pa‐
rameters were lower in OMT‐exposed newborns compared to new‐
borns in the general population (Table S2).
4 | DISCUSSION
In this study, we aimed to increase knowledge about the safety of OMT during pregnancy by examining neonatal outcomes concern‐
ing use of OMT during pregnancy using relevant comparison groups in two nationwide cohorts of pregnant women. We found no sig‐
nificant differences in neonatal growth parameters (birth weight, length, and head circumference) between OMT–exposed newborns and newborns of drug‐using pregnant women not in OMT during pregnancy. These findings were consistent in both countries. In the Norwegian sample, gestational age was nearly one week longer, and the odds of preterm birth and low Apgar score were lower in the
OMT–exposed group. In the Czech Republic, these differences were not observed.
Our results on growth parameters are in contrast to previous research,10 which suggest better neonatal outcomes in children of mothers in OMT compared to children of women with opioid use disorders not in OMT. There can be several explanations for these differences, such as the more recent study period in the present study, the European setting, the use of different comparison groups, and the registry data design of our study.
Performing studies on safety of prenatal OMT exposure in an‐
other setting than in the United States, where the majority of early research has been conducted, might reduce the role of unmea‐
sured confounding. In Norway and the Czech Republic, socioeco‐
nomic differences in the population are smaller than in the United States, and health care services are freely available for everyone.
Thus, while opioid–dependent women in these countries have low socioeconomic status, they do not live in pronounced poverty.
In this study, we tried to identify comparison groups with quite similar risk factor profiles as women in OMT. The comparison group in the Czech Republic did not differ from the OMT group Norway
OMT (n = 235) No OMTa (n = 294)
n % 95% CI n % 95% CI
Age, y
≤24 18 7.7 4.7‐12.0 64 21.8 17.3‐27.0
25‐29 70 29.8 24.1‐36.1 84 28.6 23.6‐34.2
30‐34 89 37.9 31.7‐44.4 80 27.2 22.3‐32.8
≥35 58 24.7 19.4‐30.8 66 22.4 17.9‐27.7
Marital status
Not married 91 38.7 32.5‐45.3 115 39.1 33.5‐45.0
Married/living
with partner 142 60.4 53.8‐66.7 175 59.5 53.7‐65.1
Unknown <4 4 1.4 0.4‐3.7
Education
Primary 168 71.5 65.2‐77.1 147 50.0 44.2‐55.9
Secondary 59 25.1 19.8‐31.3 78 26.5 21.7‐32.0
University 5 2.1 0.8‐5.2 48 16.3 12.4‐21.2
Unknown <4 21 7.1 4.6‐10.9
Smoking during pregnancy
Yes 161 68.5 62.1‐74.3 168 57.1 51.3‐62.8
No 27 11.5 7.8‐16.4 62 21.1 16.7‐26.3
Unknown 47 20.0 15.2‐25.8 64 21.8 17.3‐27.0
Deliveries by multiplicity
Single 229 97.4 94.3‐99.0 287 97.6 94.9‐99.0
Twins and more 6 2.6 1.0‐5.7 7 2.4 1.0‐5.1
<4 denotes less than four individuals in the group, exact numbers are not shown because of regula‐
tion from the Registries CI, confidence interval.
aWomen who gave birth to a child with neonatal abstinence syndrome
TA B L E 2 Socioeconomic characteristics of Norwegian women with indications of opioid dependence who received opioid maintenance treatment (OMT) or not during pregnancy (2004‐2013)
concerning background characteristics. In Norway, the women in OMT smoked more and had lower education. If background char‐
acteristics play an important role in affecting neonatal outcomes, the similar characteristics of the OMT and the comparison groups in our study suggest that the selected comparison groups were suitable for studying adverse outcomes of OMT during pregnancy.
However, it should be noted that the comparison groups were iden‐
tified by different criteria. In the Czech Republic, women with at least one diagnosis indicating drug dependence during pregnancy constituted the comparison group, while women who gave birth to
a newborn with NAS comprised the comparison group in Norway.
This difference combined with different treatment settings 23 can increase the generalizability of the findings. Nevertheless, the dif‐
ference between the comparisons groups might have resulted in heavier opioid users constituting the comparison group in Norway, explaining the more positive effects of OMT in Norway than in the Czech Republic.
There were differences in gestational age, preterm birth, and Apgar score between the OMT–exposed and the nonexposed group in Norway. Recent reviews report that gestational age should be TA B L E 3 Birth outcomes in newborns of women with indications of opioid dependence who either were in opioid maintenance
treatment (OMT) or not during pregnancy in the Czech Republic (2000‐2014) and Norway (2004‐2013). Singleton pregnancy only
Czech Republic Norway
OMT (n = 324) No OMTb (n = 106) OMT (n = 229) No OMTc (n = 287)
Mean SD Mean SD Mean SD Mean SD
Gestational aged (wk) 38.4 2.6 38.4 2.6 39.1 2.1 38.2 3.0
Birth weighte (g) 3056 469 3081 404 3304 507 3286 507
Birth lengthe (cm) 48.3 2.4 48.3 2.4 49.0 2.5 49.0 2.2
Head circumferencee (cm) 33.8 1.7 33.5 1.5 34.6 1.5 34.7 1.4
n % (95% CI) n % (95% CI) n % (95% CI) n % (95% CI)
Abortion induced
Yes — — — — <4 — 0 0.0 (0.0‐1.3)
No — — — — 226 98.7 (95.9‐99.7) 287 100 (98.7‐100)
Miscarriage
Yes — — — — <4 — 0 0.0 (0.0‐1.3)
No — — — — 227 99.1 (96.5‐99.8) 287 100 (98.7‐100)
Cesarean sectiond
Elective 18 5.6 (3.5‐8.9) 4 3.8 (1.2‐10.1) 25 11.0 (7.4‐16.0) 27 9.4 (6.4‐13.5)
Acute 40 12.5 (9.2‐16.7) 11 10.6 (5.7‐18.5) 26 11.5 (7.8‐16.5) 45 15.7 (11.8‐20.5)
Stillbirth 4 1.2 (0.4‐3.2) 2 1.9 (0.3‐7.3) <4 — 0 a
Preterm birthd 54 16.9 (13.0‐21.5) 15 14.4 (8.6‐23.0) 16 7.0 (4.2‐11.4) 43 15.0 (11.2‐19.8) Small for gestational aged
(SGA)
43 13.4 (10.0‐17.8) 10 9.6 (5.0‐17.4) 15 6.6 (3.9‐10.9) 23 8.0 (5.3‐11.9)
Apgar scored < 7 at 1 min
Yes 28 8.8 (6.0‐12.5) 3 2.9 (0.7‐8.8) 13 5.9 (3.3‐10.1) 33 11.5 (8.2‐15.9)
No 292 91.3 (87.5‐94.0) 101 97.1 (91.2‐99.3) 207 90.4 (85.6‐93.7) 254 88.5 (84.1‐91.8)
Apgar scored < 7 at 5 min
Yes 7 2.2 (1.0‐4.7) 2 1.9 (0.3‐7.5) 4 1.8 (0.6‐4.9) 19 6.6 (4.1‐10.3)
No 313 97.8 (95.3‐99.0) 102 98.1 (92.5‐99.7) 217 98.2 (95.1‐99.4) 268 93.4 (89.7‐95.9)
Neonatal abstinence syndrome (NAS)d
Yes — — — — 120 54.1 (47.3‐60.7) 287 a
No — — — — 102 45.9 (39.3‐52.7) 0 a
Abbreviations: CI, confidence interval; SD, standard deviation.
– data were not available for the Czech republic sample or there were less than four individuals in the Norwegian sample
aGiven selection of comparison group in Norwegian sample not relevant to calculate
bNewborns born by women hospitalized with an ICD‐10 F11 diagnosis (opioid related disorders) as primary or secondary diagnosis during pregnancy who were not in OMT during pregnancy
cNewborns born with neonatal abstinence syndrome (NAS) by women who were not in OMT during pregnancy
dLive births
eGestational age ≥ 37 weeks
considered as a continuum concerning the risk and severity of ad‐
verse outcomes.27,28 Even though the mean gestational age was within the range of term pregnancies in both the OMT groups and the comparison groups, it was almost one week longer in the OMT group than in the comparison group in Norway – even after adjust‐
ing for smoking and other sociodemographic factors. In Norway, OMT was also associated with reduced odds of preterm birth. These differences were not observed in the Czech sample. As mentioned above, a possible explanation may be that the Norwegian compar‐
ison group consisted of heavier drug–using mothers than in the Czech Republic. Further, a larger proportion of the Norwegian com‐
parison group was reported to be smoking during pregnancy than in the Czech comparison group, and it is known that smoking during pregnancy increases the risk of prematurity.29 OMT was also asso‐
ciated with reduced odds of low Apgar score only in Norway. This difference may also be explained by the differences in comparison
groups in the two countries. In the Czech Republic, the comparison group could include women who were abstinent during the last stage of the pregnancy.30 In contrast, the Norwegian group consisted of women whose children were born with NAS, indicating that the women were using drugs, quite likely opioids, up until the end of the pregnancy. This might have resulted in newborns being under the in‐
fluence of maternal opioid use shortly after delivery, and this might have influenced the Apgar score in a negative direction.
4.1 | Methodological considerations
Using information from the nationwide registries reduces the risk of selection and recall bias. By using registry data, all pregnant women are identified and followed‐up unless they move out of the country. This reduces the problem of selection both due to inclu‐
sion and to loss to follow‐up that might be especially important for
Czech republic Norway
OMT vs No OMT (ref.) OMT vs No OMT (ref.)
ba 95% CI ba 95% CI
Gestational aged
Unadjusted 0.03 0.60 to 0.55 0.93 (0.94)f 0.47‐1.39
Adjustedc 0.02 0.66 to 0.62 0.96 0.39‐1.53
Birth weighte
Unadjusted 24.6 133.9 to 84.7 18.6 75.6 to 112.7
Adjustedc 26.6 149.1 to 96.0 62.2 50.8 to 175.1
Birth lengthe
Unadjusted 0.02 0.56 to 0.60 0.05 0.40 to 0.50
Adjustedc 0.04 0.61 to 0.68 0.18 0.33 to 0.70
Head circumferencee
Unadjusted 0.30 0.16 to 0.74 0.13 0.41 to 0.15
Adjustedc 0.23 0.24 to 0.70 0.06 0.41 to 0.30
ORb 95% CI ORb 95% CI
Preterm birthd
Unadjusted 1.21 0.65‐2.24 0.44 (0.38)f 0.24‐0.81
Adjustedc 1.25 0.63‐2.46 0.35 0.16‐0.75
Small for gestational age (SGA)d
Unadjusted 1.46 0.71‐3.02 0.83 0.42‐1.63
Adjustedc 1.43 0.64‐3.18 0.58 0.26‐1.33
Apgar scored < 7 at 5 min
Unadjusted 1.14 0.23‐5.58 0.26 (0.21)f 0.09‐0.76
Adjustedc 0.92 0.16‐5.47 0.21 0.06‐0.78
significant findings are shown in bold
ab (regression coefficients) from linear regression
bOdds ratio (ORs) from binary logistic regression
cAdjusted for age, marital status, education, smoking
dLive births
eGestational age ≥ 37 weeks
fThe b or OR from crude regression analysis when restricted to the same study sample as in ad‐
justed analysis
TA B L E 4 Lineara and binary logistic regressionb comparing opioid maintenance treatment (OMT) to no such treatment during pregnancy in women with indications of opioid dependence in the Czech Republic (2000‐2014) and Norway (2004‐2013). Singleton pregnancies
pregnant women with opioid use disorders who more often have a transient lifestyle.12 Another strength with this approach is that health registries identify more women in OMT than can feasibly be included in clinical samples. While the samples of pregnant women in OMT in our study are among the largest to date, even larger samples are needed to study rare outcomes such as stillbirths and miscarriages.
The Norwegian Prescription Database only includes information on prescription drugs dispensed to outpatients. If a pregnant woman received all her OMT drugs during pregnancy at hospital or institu‐
tion, this would not have been registered in the prescription data‐
base, and we would not have identified the woman as in OMT. We assume that this is the situation for a limited number of women in OMT.22 Some critical information such as smoking is underreported in the registries. Furthermore, some data like for instance use of al‐
cohol and illicit drugs are not collected in the Norwegian registries.
In Norway, we used women who gave birth to children with NAS as the comparison group. Although it is not possible to attribute the cause of NAS to opioid exposure alone, opioids are the most common cause of NAS.31 Moreover, even though the women in the Norwegian comparison group might not have used opioids, but other drugs, they were much more similar to the pregnant women in OMT than pregnant women in the general population were and therefore more suitable as a comparison group.
Neonatal growth parameters in the OMT–exposed newborns were similar both to the outcomes in newborns of drug–depen‐
dent women not in OMT during pregnancy and to the groups of women using OMT outside of pregnancy, but not during pregnancy.
However, when compared to the general population, all the new‐
borns of women who had any indications of drug abuse before, during or after pregnancy, seem to have worse neonatal outcomes – regardless of whether the woman received OMT during preg‐
nancy or not. Taken together, this might suggest that it is not the OMT drugs themselves that are associated with worse neonatal out‐
comes, but other factors related to opioid use, such as comorbidity, socioeconomic, and lifestyle factors.
Some critics have questioned the rationale for public health care services offering opioid maintenance treatment (OMT) during pregnancy. Our findings did not suggest that OMT results in worse outcomes for the newborns compared to no treatment. Moreover, we observed some important positive neonatal outcomes from OMT versus no OMT in the Norwegian sample. Seen in conjunction with the beneficial effects for the pregnant woman such as improved pre‐
natal care adherence and obstetrical outcomes,2,32‐34 our findings support the prescription of OMT drugs to pregnant women with opioid use disorders.
ACKNOWLEDGEMENT
The study was supported by the Ministry of Health of the Czech Republic, grant No. 16‐28157A and an institutional support no.
PRVOUK‐P03/LF1/9. The Scandinavian cohort study has received grants from the Norwegian Research Council, Grant no. 240197/
H10. The funding sources were not involved in the study de‐
sign, the collection of data, analysis, interpretation of data, writ‐
ing of the manuscript, or the decision to submit the article for publication.
DISCLOSURES
None of the authors has anything to disclose.
ORCID
Marte Handal https://orcid.org/0000‐0003‐1773‐0184
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SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting Information section at the end of the article.
How to cite this article: Handal M, Nechanská B, Skurtveit S, et al. Prenatal exposure to opioid maintenance treatment and neonatal outcomes: Nationwide registry studies from the Czech Republic and Norway. Pharmacol Res Perspect.
2019;e00501. https ://doi.org/10.1002/prp2.501
